In order to execute site-isolated (parallel, serial, and combinations thereof) processing of regions of a substrate (such as but not limited to blanket wafers, patterned wafers, substrates including devices, functional chips, functional devices, and test structures, etc.) without cross-contamination between reactors and/or regions, each reactor and/or region must be effectively isolated from neighboring reactors and/or regions. Typical sealing mechanisms for full scale reactors (e.g. face seals using o-rings) are not well-suited to this task. This is because these seals require a large compressive force and depend solely on the compliance of the o-ring to provide the liquid or gas seal. Also, these seals typically do not use the processed substrate (e.g. silicon) as a sealing surface. As a result, the manufacturing tolerance and the contamination properties are of secondary concern. Therefore there is a need for sealing systems and methods that effectively seal isolated sites during site-isolated substrate processing.